Project 1 A growing body of literature shows that brain-derived neurotrophic factor (BDNF) plays a significant role in the development of the nervous system, as well as in activity-dependent learning and plasticity. BDNF levels increase over development and peak at adolescence, before beginning a steady decline that continues into adulthood. This pattern of change in BDNF levels suggests that behavioral and neuroanatomical differences between BDNF genotypes may vary across the course of development. This project examines how the uniquely-human BDNF Val66Met polymorphism mediates contextual, cued and reversal learning (extinction). Preliminary imaging studies confirm that the forms of learning under investigation are in part dependent on the hippocampus (Amso et al., 2005), amygdala (Hare et al., 2005) and ventromedial prefrontal cortex (including orbitofrontal cortex). These regions have been shown to be sensitive to environmental factors (stress) and may be compromised in children with clinical disorders (Thomas et al., 2001). We will use these behavioral learning assays in combination with structural and functional magnetic resonance imaging techniques to examine changes associated with BDNF genotype. We will specifically examine whether differences between genotypes change with age as a function of variations in BDNF levels overdevelopment (Center Aim 1). We will also determine whether mild to moderate environmental risk factors experienced over the course of typical development, as opposed to severe early stressors examined in Projects II and III, serve to potentiate differences between BDNF genotypes (Center Aim 2). This project is directly complemented by Project III, which will use similar assays in a BDNF knock-in mouse model of the human Val66Met mutation to constrain human findings with evidence from histological and cellular levels of analysis. Project I will establish the role of BDNF in the typical developmental trajectory of different forms of learning and will provide a solid foundation on which to base interpretations of BDNF gene-environment interactions in a population of adolescents who experienced severe early-life stress in the form of institutional/orphanage rearing (Project II). Both the Analytic and Data Management Core and Statistical Genetics Core will support data processing and analysis of behavioral, imaging and genetic data.